Two types of postsynaptic ionotropic glutamate receptors are stimulated by glutamate released at synapses at many sites of mammalian forebrain. These two types of receptors are usually referred to as DL-α-amino-3-hydroxy-5-methyl-4-isoxazolyl propionic acid (AMPA) receptors and N-methyl-D-aspartic acid (NMDA) receptors. AMPA receptors mediate a voltage independent fast excitatory post-synaptic current (the fast EPSC), whereas NMDA receptors generate a voltage-dependent, slow excitatory current. Studies carried out in slices of hippocampus or cortex indicate that the AMPA receptor mediated fast EPSC is generally the dominant component at most glutamatergic synapses, and the activity of AMPA receptors is usually a prerequisite for the activity of NMDA receptors.
AMPA receptors are expressed throughout the central nervous system. As reported by Monaghan et al., these receptors are found in high concentrations in the superficial layers of neocortex, in each of the major synaptic zones of hippocampus, and in the striatal complex (Monaghan et al., Brain Research, 324: 160-164 (1984)). Studies in animals and humans indicate that these structures organize complex perceptual-motor processes and provide the basis for higher-level behaviors. Thus, AMPA receptors mediate transmission in those brain networks responsible for a lot of cognitive activities. In addition, AMPA receptors are expressed in a brain region that regulates inspiratory driving responsible for controlling respiration (Paarmann et al., Journal of Neurochemistry, 74: 1335-1345 (2000)).
Therefore, drugs that modulate and thereby enhancing the function of AMPA receptors could have significant benefits for intellectual performance as well as reversal of respiratory depression induced by medication such as opioids and opiates, or other ways. Such drugs may also be beneficial for memory encoding. Experimental studies, such as those reported by Arai and Lynch, Brain Research 598:173-184 (1992), indicate that increasing the size of AMPA receptor-mediated synaptic response(s) enhances the induction of long-term potentiation (LTP). LTP is a stable increase in the strength of synaptic connection generated follows repetitive physiological activities occurring in the brain in the process of learning.
Compounds that enhance the function of the AMPA subtype of glutamate receptors facilitate the induction of LTP and the acquisition of learned tasks as measured by a number of paradigms. See, for example, Granger et al., Synapse 15:326-329 (1993); Staubli et al., PNAS 91:777-781 (1994); Arai et al., Brain Res. 638:343-346 (1994); Staubli et al., PNAS 91:11158-11162 (1994); Shors et al., Neurosci. Let. 186:153-156 (1995); Larson et al., J. Neurosci. 15:8023-8030 (1995); Granger et al., Synapse 22:332-337 (1996); Arai et al., JPET 278:627-638 (1996); Lynch et al., Internat. Clin. Psychopharm. 11:13-19 (1996); Lynch et al., Exp. Neurology 145:89-92 (1997); Ingvar et al., Exp. Neurology 146:553-559 (1997); Hampson, et al., J. Neurosci. 18:2748-2763 (1998); Porrino et al., PLoS Biol 3(9): 1-14 (2006) and Lynch and Rogers, U.S. Pat. No. 5,747,492. There is a considerable body of evidence showing that LTP is the substrate of memory. For example, compounds that block LTP interfere with memory formation in animals, and certain drugs that disrupt learning in humans antagonize the stabilization of LTP, as reported by del Cerro and Lynch, Neuroscience 49: 1-6 (1992). Learning a simple task induces LTP in hippocampus that occludes LTP generated by high frequency stimulation (Whitlock et al., Science 313:1093-1097 (2006)) and a mechanism that maintains LTP sustains spatial memory (Pastalkova, et al., Science 313:1141-1144 (2006)). Of significant importance to the field of learning is the finding that in vivo treatments with a positive AMPA-type glutamate receptor modulator restores stabilization of basal dendritic LTP in middle-aged animals (Rex, et al., J. Neurophysiol. 96:677-685 (2006)).
Drugs that enhance the functioning of the AMPA receptor can effectively reverse opioid- and barbiturate-induced respiratory depression without reversing the analgesic response (Ren et al, American Journal of Respiratory and Critical Care Medicine, 174: 1384-1391 (2006). Therefore these drugs may be useful in preventing or reversing opioid-induced respiratory depression and in alleviating other forms of respiratory depression including sedative use and sleep apnea. Excitatory synaptic transmission provides a major pathway by which neurotrophins are increased within specific brain regions. As such, potentiation of AMPA receptor function by modulators has been found to increase levels of neurotrophins, particularly brain derived neurotrophic factor, or BDNF. See, for example, Lauterborn, et al., J. Neurosci. 20:8-21 (2000); Gall, et al., U.S. Pat. No. 6,030,968; Lauterborn, et al., JPET 307:297-305 (2003); and Mackowiak, et al., Neuropharmacology 43:1-10 (2002). Other studies have linked BDNF levels to a number of neurological diseases, such as Parkinson's disease, Attention Deficit Hyperactivity Disorder (ADHD), autism, Fragile-X Syndrome, and Rett Syndrome (RTT). See, for example, O'Neill, et al., Eur. J. Pharmacol. 486:163-174 (2004); Kent, et al., Mol. Psychiatry. 10:939-943 (2005); Riikonen, et al., J. Child Neurol. 18:693-697 (2003) and Chang, et al., Neuron 49:341-348 (2006). Thus, AMPA receptor synergists may be useful for the treatment of these diseases, as well as other neurological diseases resulted from an imbalance of glutamatergic or a deficit in the neurotrophin.
A class of AMPA receptor synergist can be substituted benzamides, including, for example, 6-(piperidin-1-yl-carbonyl)quinoxaline (CX516; Ampalex®). CX516 is active in animal tests for the detection of active drugs for the treatment of memory disorder, schizophrenia, and depression. In three separate clinical trials, CX516 showed evidence for the efficacy in improving various forms of human memory (Lynch et al., Internat. Clin. Psychopharm. 11:13-19 (1996); Lynch et al., Exp. Neurology 145:89-92 (1997); Ingvar et al., Exp. Neurology 146:553-559 (1997)).
Another class of AMPA receptor synergist, benzoxazines, has been discovered to have extremely high activity in vitro and in vivo models for assessing the probability of exerting cognition enhancement (Rogers and Lynch; U.S. Pat. No. 5,736,543). The substituted benzoxazines are rigid benzamide analogues with different receptor modulating properties from the flexible benzamide, CX516.
Certain substituted 2,1,3-benzoxadiazole compounds have been found significantly and surprisingly more potent in animal models of attention deficit hyperactivity disorder (ADHD), schizophrenia and cognition than previously disclosed compounds in US 2002/0055508 and US 2002/0099050. The new N,N-disubstituted amides (I) display significant activity for enhancing AMPA mediated glutamateric synaptic responses, and many of the compounds have entered into clinical research.
The compound N-(anti-4-hydroxycyclohexyl)-N-methylbenzo[c][1,2,5]oxadiazol-5-yl-carboxamide (Compound a) is a substituted 2,1,3-benzoxadiazole. It has extremely high activity (WO2008143963). After intraperitoneal injection, it leads to a 21% increase in the amplitude of the field EPSP in the rat dentate gyrus. The compound is far more active than CX516, which gave a 9% increase in amplitude of the field EPSP after intraperitoneal injection. The compound exhibited 100% inhibition of hyperactivity induced by intraperitoneal injection of 2 mg/kg d-amphetamine.

Although this class of compounds has a good activity, the clinical doses thereof are high and close to the maximum tolerated dose. For example, the clinical dose of CX717 is up to 1500 mg/d, and the clinical dose of CX1739 is also 900 mg/d. High doses can cause serious side effects. The reason is mainly due to the wide distribution of the drug in vivo. When a drug is mainly distributed in the peripheral organs, toxicity and side effects are easily produced, and at the same time, the ratio of the drug distributed in the brain tissue is decreased, reducing the efficacy of the drug.